Environmentally benign synthesis of substituted iodinated flavones as precursors for prenyl-/geranyl flavones from the corresponding chalcones European Journal of Chemistry 15 (4) (2024) 332-337 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2024 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.15.4.332-337.2600 European Journal of Chemistry View Journal Online View Article Online Environmentally benign synthesis of substituted iodinated flavones as precursors for prenyl-/geranyl flavones from the corresponding chalcones Sumaiya Khan 1, Umme Aiman Liza 1,*, Dipan Banik 1, Md Aman Ullah Aman 1, Kamrunnahar Happy 2, Amit Chandra Arjaya 1, and Mohammad Mamun Hossain 1 1 Department of Chemistry, Faculty of Mathematical and Physical Sciences, Jahangirnagar University, Savar, Dhaka-1342, Bangladesh 2 Department of Textile Engineering, Uttara University, Holding 77 Beribadh Road, Dhaka-1230, Bangladesh * Corresponding author at: Department of Chemistry, Faculty of Mathematical and Physical Sciences, Jahangirnagar University, Savar, Dhaka-1342, Bangladesh. e-mail: aimanliza@juniv.edu (U.A. Liza). 10.5155/eurjchem.15.4.332-337.2600 Received: 1 October 2024 Received in revised form: 6 November 2024 Accepted: 17 November 2024 Published online: 31 December 2024 Printed: 31 December 2024 Flavones have biological properties because of the existence of oxoheterocyclic ring moieties, and day by day create research interest areas because of their important biological activity. Iodine-substituted flavones were synthesized from the corresponding chalcones through an exhaustive iodination reaction. Generally, it is seen that halogenated flavones show better biological activity. Moreover, the introduction of iodine in the ring moiety facilitates the incorporation of highly active side chains, such as prenyl and geranyl groups through the formation of C-C bonds by numerous coupling reactions such as Sonogashira coupling. To achieve such target molecules, a planned chemical synthesis was conducted. For comparison, microwave irradiation (MWI) and conventional heating (CH) methods were used to synthesize a series of iodine-substituted flavone compounds with different substitutes (4a-d) from their corresponding chalcones (3a-d). Unfortunately, 3e chalcone (1- hydroxynapthalene substituted flavone) did not convert to 4e flavones. In the microwave method, a notable decrease in time required in the reaction and an increase in % yield of the reaction were remarked. Characterization and conformation of all synthesized compounds were done using ultraviolet, infrared, and nuclear magnetic resonance spectroscopy and elemental analysis. Iodine Flavones Prenyl flavones Geranyl flavones Biological activity Sonogashira coupling Cite this: Eur. J. Chem. 2024, 15(4), 332-337 Journal website: www.eurjchem.com 1. Introduction Flavonoids are naturally obtained compounds that are widely distributed in the plant kingdom. Flavonols, flavones, flavanones, isoflavones, and chalcones are the classification of flavonoids according to the molecular structure [1,2]. Due to the various functions of flavones in plants and the different roles they play when they interact with other organisms, flavone compounds have inherent applications in the sectors of human health, pharmacology, and agriculture [3-5]. From the leguminosa or bean family, flavones are manufactured and used as a dietary complement. The flavonoid contains a coumarin nucleus that is a heteroaromatic part with different types of substituents that give excellent structural patterns for flavonoids. These types of phytochemicals, such as flavonoids, have extensive biological properties [6-8]. Prenylatedpoly- phenols have a characteristic nature that shows biological activity, for example, antifungal, antioxidant, anticancer, and insecticidal properties. Furthermore, soyisoflavones and prenyl have the capability for harmonious and/or other chemo- prevention therapies against long-term diseases such as menopause [9-12]. Due to their wide-range properties, flavones have attracted considerable attention in the area of cosmetics, food supplements, agrochemicals, and medicine in recent years [13,14]. Soy isoflavones such as genistein and daidzein, and their respective glycosidic conjugates of daidzein and genistein play a potential role in reducing the risk of lung, head and neck, prostate, and breast cancer for these compounds have received considerable attention from researchers [15,16]. Kato et al. published a report that both genistein, as well as daidzein, have anticancer effects against prostate cancer development at relatively early stages. Various studies suggested that genistein exerting antiproliferative effect depressed prostate cancer through the suppression of telomerase activity in prostate cancer cells. Telomerase activity is repressed by decreasing telomerase reverse transcriptase in human (hTERT) trans- criptional activity and by post-translational modification of hTERT, which is carried out by genistein exerting antiproliferative effect [17,18]. Against Gram-positive and Gram-negative bacteria, various natural polyphenolics have shown considerable high activity that was reported in recent years. Therefore, it is suggested that the substitution of the coumarine ring might be an essential requirement for biological activity [19-21]. Such types of polyphenolics derivatives exhibit high activity for that the synthesis of suitable prenylflavones is a big challenge and ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.15.4.332-337.2600 https://www.eurjchem.com/ https://dx.doi.org/ mailto:aimanliza@juniv.edu http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.15.4.332-337.2600&domain=pdf&date_stamp=2024-12-31 Khan et al. / European Journal of Chemistry 15 (4) (2024) 332-337 333 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.332-337.2600 Scheme 1. Synthesis of compounds 1, 3a-c, 4a-c. creates attention of the synthetic chemistry community. Therefore, some well-documented methods of synthesizing such a class of molecules were adopted using the microwave protocol in addition to the classical heating methodology. Consequently, a plethora of new compounds have been synthesized. Most importantly, this study aims to synthesize different substituted iodinated flavones with appreciable biological activity from iodinated chalcones and a comparative study between microwave irradiation (MWI) and conventional heating (CH) methods in synthesizing these flavones. 2. Experimental 2.1. Instrumentation Fisher-John’s electro-thermal melting point apparatus was used to determine the melting points. IR spectra were recorded by the NICOLET iS10 IR spectrophotometer on the KBr disc. A 400 MHz AVANCE Bruker NMR spectrometer was used to measure 1H-NMR spectra using solvent CDCl3 and TMS as internal standard at the Wazed Miah Science Research Center, Jahangirnagar University, Savar, Bangladesh. Parts per million (ppm) is used as units of chemical shift. The elemental analysis for carbon, hydrogen, and nitrogen was performed by the machine Elementar (Model no. Vario El Cube). The Shimadzu UV-1800 UV spectrophotometer was used to record ultraviolet spectra. The purity of the synthesized compounds was checked by TLC (silica gel-G). The TLC spots were visualized under an ultraviolet lamp and developed in an iodine chamber. 2.2. Synthesis 2.2.1. Synthesis of 1-(2-hydroxy-3, 5-diiodophenyl)ethan-1- one (1) 2.2.1.1. Microwave irradiation (MWI) method In a two-necked round-bottom flask, (1.48 g, 10.88 mmol) 2-hydroxyacetophenone was dissolved in 8 mL of EtOH solvent, (2 g, 7.88 mmol) I2 (iodine) and (0.82 g, 4.02 mmol in 7 mL of water) orthoperiodic acid were added one by one, respectively. The reaction mixture was irradiated for 8 min (5 sec × 32 times, 1 min interval/irradiation) under microwave irradiation (MWI). The mobile phase in TLC (EtOAc: n-hexane = 1:5) was used to monitor the reaction. The mixture was treated with cold distilled water to separate the solid products. Crude product was recrystallized using ethanol as a suitable solvent. A needle- shaped pale-yellow crystalline compound was obtained as a target compound [22,23]. 2.2.1.2. Conventional heating (CH) method In a two-necked round-bottom flask, (1.48 g, 10.88 mmol) 2-hydroxyacetophenone was dissolved in 12 mL of EtOH solvent, (2 g, 7.88 mmol) I2 (Iodine) and (0.82 g, 4.02 mmol in 7 mL of water) orthoperiodic acid were added one by one, respectively. Subsequently, the reaction mixture was stirred for approximately 6 hours at 55 to 60 °C. The mobile phase in TLC (EtOAc: n-hexane = 1:5) was used to monitor the reaction. The mixture was treated with cold distilled water to separate the solid product. Crude product was recrystallized using ethanol as a suitable solvent. A needle-shaped, pale-yellow-colored, crystalline compound was obtained as a target compound (Schemes 1 and 2). The comparison of MWI and CH methods is given in Table 1. 1-(2-Hydroxy-3, 5-diiodophenyl)ethan-1-one (1): Color: Pale yellow crystalline solid. Yield: 77 % (MWI). M.p.: 120-121 °C. UV (EtOAc, λmax, nm (log ε)): 365.5 (1.145). FT-IR (KBr, ν, cm-1): 3441 (OH) (br, phenol), 3039 (C-H) (aromatic), 1569 (C=C) (aromatic), 1639 (C=O). 1H-NMR (400 MHz, CDCl3, δ, ppm): 13.10 (s, 1H, ArOH), 8.23 (d, 1H, Jo = 2Hz, Ar-H), 8.02 (d, 1H, Jm = 2Hz, Ar-H), 2.67 (s, 3H, COCH3). Anal. calc. for C8H6l2O2: C, 24.77; H, 1.56. Found: C, 24.98; H, 1.51%. 2.2.2. Synthesis of compound 3a-e from compound 1 2.2.2.1. Microwave Irradiation method In a round bottom flask, an equal mole of 1-(2-hydroxy-3,5- diiodophenyl)ethan-1-one (1) (1.634 g, 3 mmol) and substituted benzaldehyde / napthaldehyde (i.e., 4-chloro- benzaldehyde, 0.4215 g, 3 mmol) mixture was dissolved in 50- 65 mL solution of alcoholic KOH (0.39 g, 7 mmol in EtOH). 334 Khan et al. / European Journal of Chemistry 15 (4) (2024) 332-337 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.332-337.2600 Table 1. Comparison of MWI and CH methods for the prepared compounds. Compound Method Reaction time Solvent (mL) Yield (%) 1 Microwave irradiation 8 min 8 77 Conventional heating 6 hours 12 64 3a Microwave irradiation 12 min 60 82 Conventional heating 60 hours 180 71 3b Microwave irradiation 15 min 60 77 Conventional heating 80 hours 160 68 3c Microwave irradiation 17 min 50 75 Conventional heating 72 hours 170 67 3d Microwave irradiation 18 min 65 78 Conventional heating 60 hours 190 70 3e Microwave irradiation 19 min 64 75 Conventional heating 62 hours 192 64 4a Microwave irradiation 10 min 12 74 Conventional heating 6 hours 25 69 4b Microwave irradiation 10 min 13 81 Conventional heating 6 hours 27 72 4c Microwave irradiation 10 min 13 75 Conventional heating 6 hours 27 67 4d Microwave irradiation 12 min 13 78 Conventional heating 6 hours 27 69 Scheme 2. Synthesis of compounds 3d-e, 4d-e. Subsequently, the reaction mixture was irradiated (10 sec × 72 times, 1 min interval/irradiation) for 12-19 minutes under MWI. The mobile phase in TLC (EtOAc: n-hexane = 1:5) was used to monitor the reaction. Then, 5% aq. HCl was added to neutralize the reaction mixture and finally ethyl acetate was used for extraction. Under reduced pressure, the solvent was removed and a semisolid mass of 2-hydroxy-chalcone was obtained. The purification of 2-hydroxychalcone was perfor- med by recrystallization from ethanol. 2.2.2.2. Conventional heating method In a round bottom flask, 0.83 mmol 1-(2-hydroxy-3,5- diiodophenyl)ethan-1-one (1) was dissolved in 20 mL of ethanol and in a beaker, 0.83 mmol of substituted benzaldehyde /napthaldehyde was dissolved in ethanol [23]. A 40% basic aqueous solution of KOH was prepared by 3.735 mmol (209 mg) of KOH. All three solutions were kept in an ice bath to cool them. After cooling, the round bottom flask was set on the magnetic stirrer (in an ice bath). Then the solution of substituted benzaldehyde/napthaldehyde was added to the solution of 1-(2-hydroxy-3,5-diiodophenyl)ethan-1-one (1) dropwise. In the next step, a 40% solution of KOH was added to the mixture dropwise. The final mixture was stirred at maximum 25 ℃, maintaining the pH at 9 for 60-80 hours. The completion of the solution was monitored by TLC (thin layer chromatography) using a solvent system of ethyl acetate and n- hexane (1:5). After completion of the reaction, the mixture was neutralized with dilute HCl (5%) and the solid mass obtained was filtered off. The crude mass was purified by recrystal- lization from ethanol. 3-(4-Chlorophenyl)-1- (2-hydroxy-3, 5-diiodophenyl)prop-2- en-1-one (3a): Colour: Yellow solid. Yield: 82% (MWI). M.p.: 155-157 °C. UV (EtOAc, λmax, nm, (log ε)): 336 (1.123). FT-IR (KBr, ν, cm-1): 3404 (OH) (br, phenol), 2997 (C-H) (aromatic), 2933(C-H) (olefinic), 1691 (C=O) (ketone), 1635 (C=C), and 1570 (Ar-CC ring). 1H NMR (400 MHz, CDCl3, δ, ppm): 13.70 (s, 1H, Ar-OH), 8.26 (d, 1H, Jm = 1.6 Hz, Ar-H), 8.16 (d, 1H, Jm = 1.6 Hz, Ar-H), 8.96 (d, 1H, Jtrans = 15.2 Hz, =C-H), 7.55 (d, 1H, Jtrans = 15.2 Hz, =C-H), 7.64 (d, 2H, Jo = 8.4 Hz, Ar-H), 7.46 (d, 2H, Jo = 8.4 Hz, Ar-H). Anal. calc. for C15H9ClI2O2: C, 35.29; H, 1.78. Found: C, 35.23; H, 1.74%. 3-(2-Chlorophenyl)-1-(2-hydroxy-3,5-diiodophenyl)prop-2- en-1-one (3b): Color: Yellowish solid. Yield: 77% (MWI). M.p.: 150-152 °C. UV (CH3OH, λmax, nm, (log ε)): 339 (0.477), 262 (0.385). FT-IR (KBr, ν, cm-1): 3435 (OH) (br, phenol), 3061 (C- H) (aromatic); 1651 (C=O) (ketone), 1544 (C=C) (alkene), 1436 (C=C) (aromatic), 1245 (C-O), 1163 (C-C), 748 (C-Cl), 545(C-I). 1H NMR (400 MHz, CDCl3, δ, ppm): 13.804 (s, 1H, Ar-OH), 8.39 (d, 1H, Jtrans = 15.6 Hz, =C-H), 8.27 (d, 1H, Jm = 1.6 Hz, Ar-H), 8.17 (d, 1H, Jm = 1.6 Hz, Ar-H), 7.84-7.82 (m, 1H, Jo = 7.6 Hz, Jm = 1.6 Hz, Ar-H), 7.55 (d, 1H, Jtrans = 15.6 Hz, =C-H), 7.52-7.50 Khan et al. / European Journal of Chemistry 15 (4) (2024) 332-337 335 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.332-337.2600 (d, 1H, Jo = 8.8 Hz, Jm = 1.6 Hz, Ar-H), 7.45-7.43 (m, 1H, Jo = 7.2 Hz, Jm= 1.6 Hz, Ar-H), 7.41-7.37 (m, 1H, Jo = 7.6 Hz, Jm = 2 Hz, Ar-H). Anal. calcd. for C15H9ClI2O2: C, 35.29; H, 1.78. Found: C, 35.21; H, 1.76%. 1-(2-Hydroxy-3,5-diiodophenyl)-3-(4-methoxyphenyl)prop- 2-en-1-one (3c): Color: Yellow crystalline solid. Yield: 75% (MWI). M.p.: 119-121 °C. UV (CH3OH, λmax, nm, (log ε)): 248 (0.445). FT-IR (KBr, ν, cm-1): 3420 (OH) (br, phenol), 3049 (C- H) (aromatic), 1637 (C=O) (ketone), 1558 (C=C) (alkene), 1423 (C=C) (aromatic), 1174 (C-O), 1149 (C-C), 538 (C-I). 1H NMR (400 MHz, CDCl3, δ, ppm): 13.12 (s, 1H, Ar-OH), 8.236 (d, 1H, Jm = 2 Hz, Ar-H), 8.18 (d, 1H, Jm = 2 Hz, Ar-H), 8.024 (d, 1H, Jtrans = 15 Hz, =C-H), 7.69 (d, 2H, Jo = 8.4 Hz, Ar-H), 7.44 (d, 1H, Jtrans = 15 Hz, =C-H), 6.99 (d, 2H, Jo = 8.4 Hz, Ar-H), 3.91 (s, 3H, Ar-O- CH3). Anal. calcd. for C16H12ClI2O3: C, 37.97; H, 2.39. Found: C, 38.01; H, 2.37%. 1-(2-Hydroxy-3,5-diiodophenyl)-3-(naphthalen-2-yl)prop-2- en-1-one (3d): Color: Yellow crystalline solid. Yield: 78% (MWI). M.p.: 138-140 °C. UV (CH3OH, λmax, nm, (log ε)): 324 (0.533). FT- IR (KBr, ν, cm-1): 3400 (OH) (br, phenol), 3047 (C-H) (aromatic), 1639 (C=O) (ketone), 1560 (C=C) (alkene), 1423 (C=C) (aromatic), 1240 (C-O), 1157 (C-C), 536 (C-I). 1H NMR (400 MHz, CDCl3, δ, ppm): 13.85 (s, 1H, Ar-OH), 8.27 (d, 1H, Jm = 2 Hz, Ar-H), 8.25 (d, 1H, Jm = 2 Hz, Ar-H), 8.18 (d, 1H, Jtrans = 15.2 Hz, =C-H), 8.13 (s, 1H, Ar-H), 8.02 (d, 1H, Jm =1.6 Hz, Jo = 12 Hz, Ar- H), 7.95 (d, 1H, Jo = 9.2 Hz, Ar-H), 7.92-7.90 (m, 1H, Ar-H), 7.83 (m, 1H, Jo = 8.4 Hz, Ar-H), 7.70 (d, 1H, Jtrans = 15.2 Hz, =C-H), 7.61-7.55 (m, 2H, Ar-H). Anal. calcd. for C19H12I2O: C, 43.38; H, 2.30. Found: C, 43.34; H, 2.24%. 1-(2-Hydroxy-3,5-diiodophenyl)-3-(1-hydroxynaphthalen-2- yl)prop-2-en-1-one (3e): Color: Yellow crystalline solid. Yield: 75% (MWI). M.p.: 135-137 °C. UV (CH3OH, λmax, nm, (log ε)): 339 (0.480). FT-IR (KBr, ν, cm-1): 3331 (OH) (br, phenol), 3049 (C- H) (aromatic), 1645 (C=O) (ketone), 1573 (C=C) (alkene), 1421 (C=C) (aromatic), 1234 (C-O), 1166 (C-C), 536 (C-I). 1H NMR (400 MHz, CDCl3, δ, ppm): 11.73 (s, 1H, Ar-OH), 8.27 (d, 1H, Jo = 8 Hz, Ar-H), 8.26 (d, 1H, Jtrans = 15.6 Hz, =C-H), 8.06 (d, 1H, Jo = 8.4 Hz, Ar-H), 7.91 (d, 1H, Jo = 8.8 Hz, Ar-H), 7.87-7.85 (m, 1H, Ar-H), 7.81 (m, 1H, Jo = 8.4 Hz, Ar-H), 7.77-7.73 (t, 1H, Jtrans = 15.6 Hz, =C-H), 7.60 (d, 1H, Jo = 8.4 Hz, Ar-H), 7.49-7.45 (m, 2H, Ar-H), 6.86 (s, 1H, Ar-OH, naphthalene). Anal. calc. for C19H12I2O3: C, 42.10; H, 2.23. Found: C, 42.08; H, 2.25%. 2.3. Synthesis of iodo-flavones (4a-e) from chalcones (3a-e) Chalcone 3a (0.402 g, 1.37 mmol) was dissolved in solvent DMSO (12 mL) and conc. H2SO4 (2-3 drops) was added to maintain pH = 2-3. After stirring the solution, a small amount of crystalline iodine was carefully added [23,24]. The reaction mixture was then irradiated for 10 min under microwave (15 sec. irradiation/interval 30 sec). Using TLC, the reaction was monitored until the reaction was complete. The reaction mixture was cooled with distilled water and extracted with chloroform (CHCl3). A 20% sodium thiosulphate aqueous solution was used to wash the organic layer and dried over anhydrous sodium sulphate. Crude diiodo-flavone 4a (Scheme 1) was recrystallized using ethylacetate as a solvent and a pure off-white crystalline solid was obtained. The same compound 4a was also synthesized by the classical heating (CH) method and it took 6 hours at a tempe- rature of 80 °C. All other iodo-flavones were also synthesized in a similar way (Schemes 1 and 2) at a temperature of 80-110 °C. However, we did not obtain the 4e compound (1-hydoxy- naphthalene substituted flavone) from 3e. The comparison of MWI and CH methods is given in Table 1. 2-(4-Chlorophenyl)-6, 8-diiodo-4H-chromen-4-one (4a): Color: Off white solid. Yield: 74% (MWI). M.p.: 206-208 °C. UV (CH3OH, λmax, nm, (log ε)): 271 (1.877). FT-IR (KBr, ν, cm-1): 3057 (C-H) (aromatic), 2939 (C-H) (olefinic), 1645 (C=O) (ketone), 1600 (C=C), 1543 (Ar CC ring). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, 1H, Jm = 2 Hz, Ar-H), 8.43 (d, 1H, Jm = 2 Hz, Ar-H), 7.98 (d, 2H, Jo = 8.4 Hz, Ar-H), 7.55 (d, 2H, Jo = 8.4 Hz, Ar-H), 6.84 (s, 1H, =C-H). Anal. calc. for C15H7ClI2O2: C, 35.46; H, 1.39. Found: C, 35.40; H, 1.35%. 2-(2-Chlorophenyl)-6, 8-diiodo-4H-chromen-4-one (4b): Color: Off-white solid. Yield: 81% (MWI). M.p.: 135-137 °C. UV (CH3OH, λmax, nm, (log ε)): 339 (0.477), 262 (0.385). FT-IR (KBr, ν, cm-1): 3061 (C-H) (aromatic), 1651 (C=O) (ketone), 1544 (C=C) (alkene), 1436 (C=C) (aromatic), 1245 (C-O), 1163 (C-C), 748 (C-Cl), 545 (C-I). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.56 (s, 1H, Ar-H), 8.45 (s, 1H, Ar-H), 8.22 (d, 1H, Jo =15 Hz, Ar-H), 7.79 (d, 1H, Jo = 6.4 Hz, Ar-H), 7.59 (t, 1H, Jo = 7.6 Hz, Ar-H), 7.54- 7.48 (m, 1H, Ar-H), 6.83 (s, 1H, =C-H). Anal. calc. for C15H7ClI2O2: C, 35.43; H, 1.39. Found: C, 35.39; H, 1.36%. 2-(4-Methoxyphenyl)-6, 8-diiodo-4H-chromen-4-one (4c): Colour: Off-white solid. Yield: 75% (MWI). M.p.: 162-165 °C. UV (CH3OH, λmax, nm, (log ε)): 323 (0.493), 258 (0.438). FT-IR (KBr, ν, cm-1): 3062 (C-H) (aromatic), 1664 (C=O) (ketone), 1508 (C=C) (alkene), 1431 (C=C) (aromatic), 1226 (C-O), 1165 (C-C), 584 (C-I). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, 1H, Jo = 2 Hz, Ar-H), 8.44 (d, 1H, Jo = 2 Hz, Ar-H), 8.04 (d, 2H, Jo = 9.2 Hz, Ar-H), 7.10 (d, 2H, Jo = 9.2 Hz, Ar-H), 6.94 (s, 1H, =C-H), 3.94 (3H, s, Ar-O-CH3). Anal. calc. for C16H10I2O3: C, 38.11; H, 2.01. Found: C, 38.08; H, 2.00%. 2-(Naphthalen-2-yl)-6, 8-diiodo-4H-chromen-4-one (4d): Colour: Off-white fluffy crystalline solid. Yield: 78% (MWI). M.p.: 175-177 °C. UV (CH3OH, λmax, nm, (log ε)): 237 (0.367), 331 (0.159). FT-IR (KBr, ν, cm-1): 3049 (C-H) (aromatic), 1647 (C=O) (ketone), 1579 (C=C) (alkene), 1431 (C=C) (aromatic), 1226 (C- O), 1163 (C-C), 543 (C-I). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.26 (d, 1H, Jm = 2 Hz, Ar-H), 8.21 (d, 1H, Jm = 2 Hz, Ar-H), 8.13 (d, 1H, Jo = 7.2 Hz Ar-H), 8.11 (d, 1H, Jm = 1.6 Hz, Ar-H), 8.03 (m, 1H, Jo = 8.4 Hz Ar-H), 7.97 (m, 1H, Jo = 8 Hz, Ar-H), 7.93 (m, 1H, Jo = 7.2 Hz, Ar-H), 7.63 (m, 2H, Jo = 8 Hz, Jo = 7.2 Hz Ar-H), 7.05 (s, 1H, =C-H). Anal. calc. for C19H10I2O2: C, 43.54; H, 1.92. Found: C, 43.50; H, 1.88%. 3. Results and discussion 2-Hydroxyacetophenone is an interesting synthetic pre- cursor in most organic reactions. Many heterocyclic compounds can be synthesized using 2-hydroxyacetophenone [25,26]. However, in the field of flavonoid chemistry, it is essential to introduce prenyl/geranyl side chains into the aromatic moiety to achieve target molecules of high potency in biological or food supplements [27]. In EtOH, 2-hydroxyacetophenone, I2, and ortho-periodic acid were dissolved. The mixture was irradiated under MW conditions to yield diiodo compound 1 with fairly good yield. The characterization of compound 1 was done using some notable physical techniques such as proton NMR. The phenolic OH proton appeared at δ 13.10 ppm as a singlet. Other peaks appeared at δ 8.23 and 8.02 ppm for two aromatic protons in the meta position having the coupling constant value Jm = 1.6 Hz. MW-assisted condensation of compound 1 with 4- chlorobenzaldehyde (2a) in a minimal amount of alcoholic KOH solution gave 3-(4-chlorophenyl)-1-(2-hydroxy-3, 5-diiodo- phenyl) prop-2-en-1-one (3a) (Scheme 1). Chalcone 3a structure was determined using 1H NMR spectral data. Two olefinic protons 1H NMR peaks at δ 8.96 and 7.55 ppm and a coupling J value of 15.2 Hz were confirmed to the trans-coupling interaction. In addition, the prominent peaks are at 13.70 for the phenolic OH proton. Two aromatic protons of the iodo-ring appeared at δ 8.26 and 8.16 ppm as doublets showing 1.6 Hz as a metacoupling constant. Other protons showed their peaks as expected. Other chalcones (3b-e) were obtained almost in a similar way in high yields, and their spectral data were found to be justified by their structural features. The next step was as crucial as it afforded the target molecules. Consequently, compound 3a by the ring closure reaction provided the desired flavone 4a in 74% yield. The reaction was carried out in the 336 Khan et al. / European Journal of Chemistry 15 (4) (2024) 332-337 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.332-337.2600 presence of the minimum amount of dimethyl sulfoxide (DMSO) as a solvent, iodine, and sulfuric acid (catalytic amount) under microwave irradiation. The evidential confirmation of the formation of flavone 4a by identifying a characteristic peak for flavone appeared at δ 6.84 ppm singlet peak for the =C-H. For the substituted phenyl (B) ring aromatic protons at δ 7.98 and 7.55 ppm a doublet pattern appeared. The splitting of the para- substituted aromatic protons showed that the coupling was found to be 8.4 Hz. Furthermore, the microanalysis results of the compound are consistent with the calculated value. Similarly, all other compounds 4b-d were synthesized in high yields which are described in the experimental section (Schemes 1 and 2). In AcOH and H2SO4 mixtures using the conventional heating method, the same ring closure reaction was also achieved. However, with the conventional method, lower yields were obtained compared to those obtained with the microwave method. Conventional heating cyclization of 2- hydroxychalcone is very useful in the presence of a catalytic amount of iodine in DMSO, but a large volume of DMSO is required for successful reaction. Periodic acid-mediated iodination of hydroxyacetophenone was easier. There are some advantages of the method, such as aryl iodide (65-90%), fair to good yield, and short reaction time (10-12 min). On the basis of spectral and elemental data, the aryl iodide structure was established. The reaction of chalcone with iodine occurred smoothly because the mode of reaction was easy. It is predicted that the reaction follows a nucleophilic path with iodine. The microwave irradiation process in the presence of iodine reagents provides a faster reaction pathway, and it also has potential from environmental and economic standpoints. Here, H2SO4 was used as a catalyst that opens a catalytic pathway to convert into a target product by comprising enhancement of the attack by the ring A, OH group on the beta (β) carbon to produce an intermediate. However, it was observed that the cyclization of chalcone 3e was unsuccessful. This is probably due to the proximity of the 2-OH group which prevented cyclization for the steric hindered position. 4. Conclusions Flavonoids are heterocyclic moiety-containing molecules that are essential in the field of food supplements and for the preparation of other bioactive compounds. Efficient methods to access these heterocycles have been very crucial recently in the field of synthesis. We report here the formation of these heterocycles and the introduction of iodine in the aromatic moiety, which practically facilitated the production of more desirable bioactive side chains such as prenyl or geranyl groups. Consequently, molecular iodine with periodic acid is being used for the synthesis of iodoflavones from their precursor 2-hydroxy chalcones. This is an exhaustive iodination for the possible way to achieve further prenylation or allylation by using Claisen-Schmidt condensation. A series of chalcones (3a-e) were synthesized for better and simple polyphenolics and related compounds. The cyclization of chalcones gave the corresponding flavones (4a-d). The results are obtained by using a minimal amount of DMSO, iodine, and a few drops of sulfuric acid. Flavones were obtained as target molecules in better yields under the microwave reaction protocol. These molecules were also synthesized under conventional heating methods. Undoubtedly, the MW procedure was much better regarding product yield, reaction time, and of course the amount of solvent. Acknowledgements The authors thank the Department of Chemistry, Jahangirnagar University, for providing chemicals and reagents, providing laboratory facilities, and contributing support. We also acknowledge the contribution of the Wazed Miah Science Research Center, Jahangirnagar University, Savar, Bangladesh, for recording the elemental and spectroscopic data of the synthesized compounds. Disclosure statement Conflict of interest: The authors have no conflict of interest that has been declared. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the authors. CRediT authorship contribution statement Conceptualization: Mohammad Mamun Hossain, Sumaiya Khan; Methodology: Sumaiya Khan, Mohammad Mamun Hossain; Validation: Sumaiya Khan, Umme Aiman Liza, Mohammad Mamun Hossain; Synthesis: Dipan Banik, Md Aman Ullah Aman, Amit Chandra Arjaya; Formal Analysis:, Sumaiya Khan, Umme Aiman Liza, Dipan Banik, Md Aman Ullah Aman, Amit Chandra Arjaya, Kamrunnahar Happy, Mohammad Mamun Hossain; Investigation: Sumaiya Khan, Dipan Banik, Mohammad Mamun Hossain; Resources: Mohammad Mamun Hossain, Sumaiya Khan, Umme Aiman Liza; Data Correction: Sumaiya Khan, Umme Aiman Liza, Dipan Banik, Md Aman Ullah Aman, Kamrunnahar Happy, Amit Chandra Arjaya, Mohammad Mamun Hossain; Writing - Original Draft: Mohammad Mamun Hossain, Sumaiya Khan, Umme Aiman Liza; Writing - Review and Editing: Mohammad Mamun Hossain, Sumaiya Khan, Umme Aiman Liza; Visualization: Mohammad Mamun Hossain, Sumaiya Khan, Umme Aiman Liza; Funding acquisition: Mohammad Mamun Hossain, Sumaiya Khan, Umme Aiman Liza; Supervision: Mohammad Mamun Hossain, Sumaiya Khan; Project Administration: Mohammad Mamun Hossain, Sumaiya Khan. Funding Jahangirnagar University, Savar, Dhaka, Bangladesh https://www.juniv.edu ORCID and Email Sumaiya Khan sumaiya9@juniv.edu https://orcid.org/0000-0003-1473-7102 Umme Aiman Liza aimanliza@juniv.edu https://orcid.org/0009-0001-5971-7001 Dipan Banik dipanbanikamit094@gmail.com https://orcid.org/0009-0009-4746-1676 Md Aman Ullah Aman aman.stu2017@juniv.edu https://orcid.org/0009-0002-3567-389X Kamrunnahar Happy k.happy@uttarauniversity.edu.bd https://orcid.org/0000-0002-0026-1855 Amit Chandra Arjaya amitaryachemju@gmail.com https://orcid.org/0009-0000-9566-6216 Mohammad Mamun Hossain chemamun@juniv.edu https://orcid.org/0000-0002-7712-2482 References [1]. Chen, S.; Wang, X.; Cheng, Y.; Gao, H.; Chen, X. A Review of Classification, Biosynthesis, Biological Activities and Potential Applications of Flavonoids. Molecules 2023, 28 (13), 4982. [2]. Santos, E. L.; Maia, B. H.; Ferriani, A. P.; Teixeira, S. D. Flavonoids: Classification, Biosynthesis and Chemical Ecology. Flavonoids - Biosynth. Hum. Health 2017, https://doi.org/10.5772/67861. [3]. Cushnie, T. T.; Lamb, A. J. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents 2005, 26 (5), 343–356. [4]. Ullah, A.; Munir, S.; Badshah, S. L.; Khan, N.; Ghani, L.; Poulson, B. G.; Emwas, A.; Jaremko, M. Important Flavonoids and Their Role as a Therapeutic Agent. Molecules 2020, 25 (22), 5243. [5]. O’Prey, J.; Brown, J.; Fleming, J.; Harrison, P. R. Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. Biochem. Pharmacol. 2003, 66 (11), 2075–2088. https://www.juniv.edu/ mailto:sumaiya9@juniv.edu https://orcid.org/0000-0003-1473-7102 mailto:aimanliza@juniv.edu https://orcid.org/0009-0001-5971-7001 mailto:dipanbanikamit094@gmail.com https://orcid.org/0009-0009-4746-1676 mailto:aman.stu2017@juniv.edu https://orcid.org/0009-0002-3567-389X mailto:k.happy@uttarauniversity.edu.bd https://orcid.org/0000-0002-0026-1855 mailto:amitaryachemju@gmail.com https://orcid.org/0009-0000-9566-6216 mailto:chemamun@juniv.edu https://orcid.org/0000-0002-7712-2482 https://doi.org/10.5772/67861 Khan et al. / European Journal of Chemistry 15 (4) (2024) 332-337 337 2024 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.15.4.332-337.2600 [6]. Panche, A. N.; Diwan, A. D.; Chandra, S. R. Flavonoids: an overview. J. Nutr. Sci. 2016, 5, https://doi.org/10.1017/jns.2016.41. [7]. Dias, M. C.; Pinto, D. C.; Silva, A. M. Plant Flavonoids: Chemical Characteristics and Biological Activity. Molecules 2021, 26 (17), 5377. [8]. Hollman, P.; Katan, M. Dietary Flavonoids: Intake, Health Effects and Bioavailability. Food Chem. Toxicol. 1999, 37 (9-10), 937–942. [9]. Patel, R. Antioxidant mechanisms of isoflavones in lipid systems: paradoxical effects of peroxyl radical scavenging. Free Radic. Biol. Med. 2001, 31 (12), 1570–1581. [10]. Marini, H.; Minutoli, L.; Polito, F.; Bitto, A.; Altavilla, D.; Atteritano, M.; Gaudio, A.; Mazzaferro, S.; Frisina, A.; Frisina, N.; Lubrano, C.; Bonaiuto, M.; D'Anna, R.; Cannata, M. L.; Corrado, F.; Adamo, E. B.; Wilson, S.; Squadrito, F. Effects of the Phytoestrogen Genistein on Bone Metabolism in Osteopenic Postmenopausal Women. Ann. Intern. Med. 2007, 146 (12), 839–847. [11]. Wangen, K. E. Effects of Soy Isoflavones on Markers of Bone Turnover in Premenopausal and Postmenopausal Women. J. Clin. Endocrinol. Amp. Metab. 2000, 85 (9), 3043–3048. [12]. Arjmandi, B. H.; Smith, B. J. Soy isoflavones’ osteoprotective role in postmenopausal women: mechanism of action. J. Nutr. Biochem. 2002, 13 (3), 130–137. [13]. Tungmunnithum, D.; Tanaka, N.; Uehara, A.; Iwashina, T. Flavonoids Profile, Taxonomic Data, History of Cosmetic Uses, Anti-Oxidant and Anti-Aging Potential of Alpinia galanga (L.) Willd. Cosmetics 2020, 7 (4), 89. [14]. Shah, A.; Smith, D. L. Flavonoids in Agriculture: Chemistry and Roles in, Biotic and Abiotic Stress Responses, and Microbial Associations. Agronomy 2020, 10 (8), 1209. [15]. Birt, D. F.; Hendrich, S.; Wang, W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol. Amp. Ther. 2001, 90 (2-3), 157–177. [16]. Lee, S.; Lim, K. C.; Shin, S. Y.; Lee, Y. H. Isoflavone derivatives inhibit NF-κB-dependent transcriptional activity. Bioorg. Amp. Med. Chem. Lett. 2010, 20 (21), 6277–6281. [17]. Rodríguez-García, C.; Sánchez-Quesada, C.; Gaforio, J. J. Dietary Flavonoids as Cancer Chemopreventive Agents: An Updated Review of Human Studies. Antioxidants 2019, 8 (5), 137. [18]. Parekh, N.; Garg, A.; Choudhary, R.; Gupta, M.; Kaur, G.; Ramniwas, S.; Shahwan, M.; Tuli, H. S.; Sethi, G. The Role of Natural Flavonoids as Telomerase Inhibitors in Suppressing Cancer Growth. Pharmaceuticals 2023, 16 (4), 605. [19]. Tsukayama, M.; Wada, H.; Kawamura, Y.; Yamashita, K.; Nishiuchi, M. Regioselective Synthesis of 6-Alkyl- and 6- Prenylpolyhydroxyisoflavones and 6-Alkylcoumaronochromone Derivatives. Chem. Pharm. Bull. 2004, 52 (11), 1285–1289. [20]. Wu, T.; He, M.; Zang, X.; Zhou, Y.; Qiu, T.; Pan, S.; Xu, X. A structure– activity relationship study of flavonoids as inhibitors of E. coli by membrane interaction effect. Biochim. Biophys. Acta (BBA) - Biomembr. 2013, 1828 (11), 2751–2756. [21]. Karak, P. Biological activities of flavonoids: An overview. Int. J. Pharm. Sci. Res. 2019, 10 (4), 1567–1574. https://ijpsr.com/bft- article/biological-activities-of-flavonoids-an-overview/ [22]. Hossain, M. M.; Kawamura, Y.; Yamashita, K.; Tsukayama, M. Microwave-assisted regioselective synthesis of natural 6- prenylpolyhydroxyisoflavones and their hydrates with hypervalent iodine reagents. Tetrahedron 2006, 62 (36), 8625–8635. [23]. Rahman, M. S.; Alam, S. S.; Happy, K.; Hossain, M. M.; Islam, M. K.; Biswas, F. B. Eco-friendly and simple synthesis of some non-natural flavones through chalcones. Eur. J. Chem. 2018, 9 (3), 236–240. [24]. Tokuoka, T.; Yamashita, K.; Kawamura, Y.; Tsukayama, M.; M. Hossain, M. Regioselective Synthesis of 6-Prenylpolyhydroxyisoflavone (Wighteone) and Wighteone Hydrate with Hypervalent Iodine. Synth. Commun. 2006, 36 (9), 1201–1211. [25]. Mohammadi Ziarani, G.; Kheilkordi, Z.; Mohajer, F. Recent advances in the application of acetophenone in heterocyclic compounds synthesis. J. Iran Chem. Soc. 2019, 17 (2), 247–282. [26]. Khan, A.; Jain, A.; Solank, M. Synthesis and Biological Evaluation of Newly Synthesized Halogenated Flavones. Orient. J. Chem 2024, 40 (2), 562–568. [27]. Kumar, D.; Kaushik, M. K. A Novel Synthesis of 2-Quinolinyl Chromones Using Grinding Technique under Solvent-Free Conditions. Russ J. Org. Chem. 2023, 59 (6), 1059–1063. Copyright © 2024 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at https://www.eurjchem.com/index.php/eurjchem/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (https://www.eurjchem.com/index.php/eurjchem/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). https://doi.org/10.1017/jns.2016.41 https://ijpsr.com/bft-article/biological-activities-of-flavonoids-an-overview/ https://ijpsr.com/bft-article/biological-activities-of-flavonoids-an-overview/ https://www.eurjchem.com/index.php/eurjchem/terms http://creativecommons.org/licenses/by-nc/4.0 https://www.eurjchem.com/index.php/eurjchem/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Synthesis 2.2.1. Synthesis of 1-(2-hydroxy-3, 5-diiodophenyl)ethan-1-one (1) 2.2.1.1. Microwave irradiation (MWI) method 2.2.1.2. Conventional heating (CH) method 2.2.2. Synthesis of compound 3a-e from compound 1 2.2.2.1. Microwave Irradiation method 2.2.2.2. Conventional heating method 2.3. Synthesis of iodo-flavones (4a-e) from chalcones (3a-e) 3. Results and discussion 4. Conclusions Acknowledgements Disclosure statement CRediT authorship contribution statement Funding ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: